This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our overall objective is to develop an atomic level understanding of the calcium release from intracellular stores via the calcium (Ca2+) release channels /ryanodine receptors (RyRs) which is required for excitation-contraction (EC) coupling in skeletal and cardiac muscle. We aim to elucidate structure-function relationships of the skeletal (RyR1) calcium release cannels. In the past few years, important advances have been achieved in terms of identifying functional domains of the channels and in understanding the role of the FK506 binding protein (FKBP also known as calstabin) in regulating RyR function. The aims of this proposal are designed to extend these observations to atomic level resolution and to expand our understanding of the mechanisms by which calstabins regulate RyRs channel function and its role in human diseases and as a drug target.